Artificial valved conduits for cardiac reconstructive procedures and methods for their production

ABSTRACT

Artificial heart valve structures and methods of their fabrication are disclosed. The heart valve structures may be fabricated from a biocompatible polymer and include one or more heart valve leaflet structures incorporated within a conduit. The valve structures may incorporate one or more conduit sinuses, as well as a gap between the lower margin of the valve leaflets and the interior of the conduit. In addition, the valve structures may include one or more valve sinuses created in a space between the valve leaflets and the conduit inner surface. Computational fluid dynamics and mechanical modeling may be used to design the valve leaflets with optimal characteristics. A heart valve structure may also incorporate a biodegradable component to which cells may adhere The incorporated cells may arise from patient cells migrating to the biodegradable component, or the component may be pre-seeded with cells prior to implantation in a patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/413,571, filed Jan. 24, 2017; which is a continuation of U.S. patentapplication Ser. No. 14/235,578, filed Apr. 1, 2014, now U.S. Pat. No.9,585,746; which is a U.S. national stage filing under 35 U.S.C. § 371of International PCT Application No. PCT/US2012/048902, filed Jul. 30,2012; which claims priority to and benefit of: U.S. ProvisionalApplication No. 61/633,634, filed Feb. 14, 2012; U.S. ProvisionalApplication No. 61/628,209, filed Oct. 26, 2011; and U.S. ProvisionalApplication No. 61/574,254, filed Jul. 29, 2011; each of which isincorporated herein by reference in its entirety.

BACKGROUND

The selection of a heart valve structure for right ventricle outflowtract (RVOT) reconstruction may present a major challenge in thetreatment of many congenital heart diseases including, withoutlimitation, tetralogy of Fallot with pulmonary atresia, truncusarteriosus, transposition of great arteries with pulmonary stenosis, andcongenital aortic stenosis/insufficiency.

Heart valve structures that may be used for RVOT reconstruction inpediatric patients may consist of homografts, which may not be readilyavailable in many cases, and xenografts, which may be expensive(frequently around 4,000-5,000). After the invention of thecryopreservation process in early 1980s, and especially with theincreased availability of a wide range of sizes, the homograft hasfrequently become the heart surgeon's heart valve structure of choicefor the RVOT reconstruction. However, longitudinal studies havedemonstrated that homografts may also necessitate heart valve structurereplacement due to stenosis and insufficiency. Such complications may becaused by shrinkage and calcification, and may be especially problematicfor younger patients.

Recently, new xenograft designs have been evaluated for RVOTreconstruction including a glutaraldehyde-fixed porcine aortic valve androot, and a glutaraldehyde-fixed segment of a bovine jugular vein withvenous valve. Although the anatomical shape of the porcine prosthesismay fit well to the RVOT, stenosis and calcification issues may stillpersist when the prosthesis is implanted in children. Similarly, recentreports on the bovine heart valve structures suggest a significant earlyfibrotic ring formation at the distal anastomosis. Additionally,dramatic dilation of and regurgitation through a heart valve structuremay occur in the setting of pulmonary hypertension or distal anastomoticring. The most successful heart valve structures for RVOTreconstruction, the homograft and the bovine jugular vein, both haveshown re-operation rates of around 10-20% after about only two years.Re-operation and re-intervention rates, especially for the bovinexenograft, appear to increase significantly with increasing time anddecreasing conduit diameter.

Both homografts and xenografts may suffer from calcification, which mayresult in stenosis and insufficiency, leading to the need forre-operation and replacement of the heart valve structure. Additionally,studies suggest that bioprosthetic heart valve structures available forRVOT reconstruction i.e. both allografts and xenografts, may beineffective due to poor hemodynamic performance and long-termcomplications, especially in very young patients. Even afterbioprosthetic valve replacement is performed, frequent surgeries forRVOT reconstruction may be required until the individual reachesadulthood. The additional surgeries may be required due to recurrentstenosis/insufficiency caused by calcification or degenerativeprocesses, as well as the relative stenosis due to somatic growth.

Artificial heart valve structures may be considered as an alternative toboth homografts and xenografts. However, artificial mechanical valvesmay not generally be available for RVOT reconstruction for pediatricpatients. One factor that may affect availability of such heart valvestructures may include the difficulty of designing a valve structurewhich can deal with the very low pressures (which may be less than 20mmHg in many cases) found in the pediatric RVOT. Additional designchallenges may also include small conduit diameter, a high degree ofcurvature along the conduit path, and the need for conduit flexibilityas the patient grows. Intensive bioengineering studies may be requiredto produce effective designs customized for the pediatric/neonatalpopulation. In use, mechanical valves may have higher longevity whenimplanted in the pulmonary position compared to implantation in theaortic position, but may require aggressive anticoagulant therapy due toa higher risk of thrombosis.

In addition to those conditions disclosed above for which RVOT isindicated, other disorders may also benefit from implanted artificialheart valve structures. Hypoplastic Left Heart Syndrome (HLHS) is a rareand complex congenital heart disorder which may be extremely difficultto treat successfully. HLHS may be characterized by a hypoplastic leftventricle that is unable to maintain systemic circulation, a hypoplasticaortic arch and ascending aorta that require reconstruction, and apatent ductus arteriosus that may maintain systemic circulation of thelower body. In order to treat HLHS, three separate procedures may berequired: a Norwood operation, a bidirectional Glenn procedure, and aFontan procedure.

The Norwood operation typically involves connecting the base of thepulmonary artery to the aortic arch in order to re-direct blood flow tothe systemic tract. In order to continue to provide circulation to thepulmonary tract, a shunt or conduit may be placed following the Norwoodoperation to provide blood flow to the pulmonary artery. At present,there are two typical options for such a shunt: a Blalock-Taussig (BT)shunt that may connect the aorta to the base of the pulmonary artery,and a Sano shunt (RV-PA conduit) that may be placed between the rightventricle and the pulmonary artery.

The placement of the BT shunt may result in blood flow from the aorta tothe pulmonary artery during both systolic and diastolic phases. Thisconstant flow due to the BT shunt may cause low systemic diastolicpressure that can potentially lead to early mortality. The RV-PA conduitmay avoid the issue of the pulmonary tract constantly leaching bloodflow from the systemic tract by connecting the pulmonary artery directlyto the right ventricle, rather than the aorta. In this manner the RV-PAshunt can maintain higher systemic diastolic pressure than the BT shunt.However present RV-PA shunts contain no valves, so backflow may occurinto the right ventricle. As a result of the backflow, right ventricularenlargement may occur leading eventually to the need for partial ortotal heart replacement.

Shunts used for the treatment of HLHS can be very small, normally havinga diameter of around 4 mm. This can make extremely difficult the designand manufacturing of any heart valve structure containing such aconduit. Past attempts at using a simple valved conduit have beenunsuccessful, as the placement and geometry of the valve have resultedin the valve sticking to the conduit. Valve sticking may result inthrombus formation and flow impedance, which often results in earlypatient mortality.

Therefore, there appears to be a significant need for a heart valvestructure, encompassing a conduit and a heart valve leaflet structure,with long durability for use with neonatal and pediatric patients.

SUMMARY

Before the present methods are described, it is to be understood thatthis invention is not limited to the particular systems, methodologiesor protocols described, as these may vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present disclosure which will be limited only by the appendedclaims.

For the purpose of this disclosure, the term “heart valve leafletstructure” may be defined as a valved structure for use in coronary orvascular procedures, which may be composed of one or more heart valveleaflets. The term may encompass, as non-limiting examples, a heartvalve single leaflet structure having a single heart valve leaflet, or aheart valve multi-leaflet structure having more than one heart valveleaflet. Each heart valve leaflet may include a sinus edge, a fan edge,a sinus structure, and a fan structure.

For the purpose of this disclosure, the term “heart valve structure” maybe defined as a valved structure for use in coronary or vascularprocedures composed of one or more heart valve leaflet structures andadditional structural components. Additional structural components mayinclude, without limitation, a conduit and one or more conduit sinusstructures. The term may encompass a single leaflet heart valvestructure having a heart valve single leaflet structure, or amulti-leaflet heart valve structure composed of either multiple heartvalve single leaflet structures or a heart valve multi-leafletstructure.

In an embodiment, a heart valve multi-leaflet structure may include afirst heart valve leaflet, having a first sinus edge and a first fanedge, and a second heart valve leaflet, having a second sinus edge and asecond fan edge, in which the first fan edge may intersect the secondfan edge at an outer commissure point, and the first sinus edge mayintersect the second sinus edge at an inner commissure point, therebyforming a commissure extending from the outer commissure point to theinner commissure point. Additionally, the first fan edge may intersectthe first sinus edge at a first outer leaflet point, thereby forming afirst baseline extending from the first outer leaflet point to thecommissure, the first baseline further having a first width as measuredfrom the first outer leaflet point to the commissure. Further, thesecond fan edge may intersect the second sinus edge at a second outerleaflet point, thereby forming a second baseline extending from thesecond outer leaflet point to the commissure, the second baselinefurther having a second width as measured from the second outer leafletpoint to the commissure. In addition, the second baseline may beessentially collinear with the first baseline. The first sinus edge mayalso extend from and may not be coextensive with the first baseline,thereby forming a first sinus structure bounded by the first sinus edge,the commissure, and the first baseline, and the second sinus edge mayextend from and may not be coextensive with the second baseline, therebyforming a second sinus structure bounded by the second sinus edge, thecommissure, and the second baseline. Further, the first fan edge mayextend from and may not be coextensive with the first baseline, therebyforming a first fan structure bounded by the first fan edge, thecommissure, and the first baseline, and the second fan edge may extendfrom and may not be coextensive with the second baseline, therebyforming a second fan structure bounded by the second fan edge, thecommissure, and the second baseline. In addition, the first heart valveleaflet may include a biocompatible and hemocompatible polymer, and thesecond heart valve leaflet may also include an effectively same thebiocompatible and hemocompatible polymer.

In an embodiment, a heart valve structure may include a conduitcomprising an inner conduit surface, an outer conduit surface, and adiameter, and a heart valve multi-leaflet structure. The heart valvemulti-leaflet structure may include a first heart valve leaflet, havinga first sinus edge and a first fan edge, and a second heart valveleaflet, having a second sinus edge and a second fan edge, in which thefirst fan edge may intersect the second fan edge at an outer commissurepoint, and the first sinus edge may intersect the second sinus edge atan inner commissure point, thereby forming a commissure extending fromthe outer commissure point to the inner commissure point. Additionally,the first fan edge may intersect the first sinus edge at a first outerleaflet point, thereby forming a first baseline extending from the firstouter leaflet point to the commissure, the first baseline further havinga first width as measured from the first outer leaflet point to thecommissure. Further, the second fan edge may intersect the second sinusedge at a second outer leaflet point, thereby forming a second baselineextending from the second outer leaflet point to the commissure, thesecond baseline further having a second width as measured from thesecond outer leaflet point to the commissure. In addition, the secondbaseline may be essentially collinear with the first baseline. The firstsinus edge may also extend from and may not be coextensive with thefirst baseline, thereby forming a first sinus structure bounded by thefirst sinus edge, the commissure, and the first baseline, and the secondsinus edge may extend from and may not be coextensive with the secondbaseline, thereby forming a second sinus structure bounded by the secondsinus edge, the commissure, and the second baseline. Further, the firstfan edge may extend from and may not be coextensive with the firstbaseline, thereby forming a first fan structure bounded by the first fanedge, the commissure, and the first baseline, and the second fan edgemay extend from and may not be coextensive with the second baseline,thereby forming a second fan structure bounded by the second fan edge,the commissure, and the second baseline. Additionally, at least aportion of the first fan edge, at least a portion of the second fanedge, and at least a portion of the inner conduit surface may bemutually disposed to form a valve gap. Further, at least a portion ofthe first sinus structure and a portion of the inner conduit surface maybe nonadjacent, thereby forming a first valve sinus bounded at least inpart by at least a portion of the inner conduit surface and at least aportion of the first sinus structure, and at least a portion of thesecond sinus structure and a portion of the inner conduit surface may benonadjacent, thereby forming a second valve sinus bounded at least inpart by at least a portion of the inner conduit surface and at least aportion of the second sinus structure.

In an embodiment, a method of fabricating a heart valve structure, mayinclude providing a flexible conduit comprising a wall, an innersurface, and an outer surface; providing a heart valve multi-leafletstructure; everting the flexible conduit; affixing the heart valvemulti-leaflet structure to the inner surface; and reverting the conduit,thereby forming a multi-leaflet valve within an interior of the conduit.a heart valve structure may include a conduit comprising an innerconduit surface, an outer conduit surface, and a diameter, and a heartvalve multi-leaflet structure. The heart valve multi-leaflet structuremay include a first heart valve leaflet, having a first sinus edge and afirst fan edge, and a second heart valve leaflet, having a second sinusedge and a second fan edge, in which the first fan edge may intersectthe second fan edge at an outer commissure point, and the first sinusedge may intersect the second sinus edge at an inner commissure point,thereby forming a commissure extending from the outer commissure pointto the inner commissure point. Additionally, the first fan edge mayintersect the first sinus edge at a first outer leaflet point, therebyforming a first baseline extending from the first outer leaflet point tothe commissure, the first baseline further having a first width asmeasured from the first outer leaflet point to the commissure. Further,the second fan edge may intersect the second sinus edge at a secondouter leaflet point, thereby forming a second baseline extending fromthe second outer leaflet point to the commissure, the second baselinefurther having a second width as measured from the second outer leafletpoint to the commissure. In addition, the second baseline may beessentially collinear with the first baseline. The first sinus edge mayalso extend from and may not be coextensive with the first baseline,thereby forming a first sinus structure bounded by the first sinus edge,the commissure, and the first baseline, and the second sinus edge mayextend from and may not be coextensive with the second baseline, therebyforming a second sinus structure bounded by the second sinus edge, thecommissure, and the second baseline. Further, the first fan edge mayextend from and may not be coextensive with the first baseline, therebyforming a first fan structure bounded by the first fan edge, thecommissure, and the first baseline, and the second fan edge may extendfrom and may not be coextensive with the second baseline, therebyforming a second fan structure bounded by the second fan edge, thecommissure, and the second baseline. Additionally, at least a portion ofthe first fan edge, at least a portion of the second fan edge, and atleast a portion of the inner conduit surface may be mutually disposed toform a valve gap. Further, at least a portion of the first sinusstructure and a portion of the inner conduit surface may be nonadjacent,thereby forming a first valve sinus bounded at least in part by at leasta portion of the inner conduit surface and at least a portion of thefirst sinus structure, and at least a portion of the second sinusstructure and a portion of the inner conduit surface may be nonadjacent,thereby forming a second valve sinus bounded at least in part by atleast a portion of the inner conduit surface and at least a portion ofthe second sinus structure.

In an embodiment, a method of fabricating a heart valve leafletstructure includes providing a set of leaflet modeling parameters to aleaflet modeling computing program, calculating a heart valve leafletstructure initial model having one or more sinus edges, one or moresinus structures, one or more sinus baselines, one or more fan edges,one or more fan structures, and one or more fan baselines, mapping theone or more sinus edges of the heart valve leaflet structure initialmodel onto the inner surface of a conduit model, dividing the one ormore sinus structures into one or more sinus structure beams,calculating the general shape of each of the one or more sinus structurebeams, sectioning each sinus structure beam into one or more sinusstructure beam point-elements in which at least a portion of the sinusstructure beam point-elements correspond to points along the one or moresinus structure baselines, mapping the one or more fan structurebaselines of the heart valve leaflet structure initial model onto thesinus structure beam point-elements correspond to points along the oneor more sinus structure baselines, dividing the one or more fanstructures into one or more fan structure beams, calculating the generalshape of each of the one or more fan structure beams, sectioning eachfan structure beam into one or more fan structure beam point-elements,creating a point-element aggregate from the fan structure beam pointelements and the sinus structure beam point-elements, calculating apoint-element aggregate mesh representation, smoothing the point elementaggregate mesh representation, calculating a solid structure model fromthe smoothed point-element aggregate mesh representation thereby forminga heart valve leaflet model, providing fluid flow parameters and thesolid structure model to a fluid flow analysis, calculating a valveperformance cost function, repeating the solid modeling and fluid flowanalyses until the valve performance cost function is minimal, andproviding a set of heart valve leaflet size parameters corresponding tothe solid model having the minimal valve performance cost functionvalue.

In an embodiment, a hybrid tissue-engineered valved conduit includes aconduit having an inner conduit surface, an outer conduit surface, adiameter, and at least one conduit breach having a first conduit breachedge and a second conduit breach edge, a heart valve multi-leafletstructure, and at least one biodegradable structure having a first sideaffixed to the first conduit breach edge and a second side affixed tothe second conduit breach edge. The heart valve multi-leaflet structuremay include a first heart valve leaflet, having a first sinus edge and afirst fan edge, and a second heart valve leaflet, having a second sinusedge and a second fan edge, in which the first fan edge may intersectthe second fan edge at an outer commissure point, and the first sinusedge may intersect the second sinus edge at an inner commissure point,thereby forming a commissure extending from the outer commissure pointto the inner commissure point. Additionally, the first fan edge mayintersect the first sinus edge at a first outer leaflet point, therebyforming a first baseline extending from the first outer leaflet point tothe commissure, the first baseline further having a first width asmeasured from the first outer leaflet point to the commissure. Further,the second fan edge may intersect the second sinus edge at a secondouter leaflet point, thereby forming a second baseline extending fromthe second outer leaflet point to the commissure, the second baselinefurther having a second width as measured from the second outer leafletpoint to the commissure. In addition, the second baseline may beessentially collinear with the first baseline. The first sinus edge mayalso extend from and may not be coextensive with the first baseline,thereby forming a first sinus structure bounded by the first sinus edge,the commissure, and the first baseline, and the second sinus edge mayextend from and may not be coextensive with the second baseline, therebyforming a second sinus structure bounded by the second sinus edge, thecommissure, and the second baseline. Further, the first fan edge mayextend from and may not be coextensive with the first baseline, therebyforming a first fan structure bounded by the first fan edge, thecommissure, and the first baseline, and the second fan edge may extendfrom and may not be coextensive with the second baseline, therebyforming a second fan structure bounded by the second fan edge, thecommissure, and the second baseline. Additionally, at least a portion ofthe first fan edge, at least a portion of the second fan edge, and atleast a portion of the inner conduit surface may be mutually disposed toform a valve gap. Further, at least a portion of the first sinusstructure and a portion of the inner conduit surface may be nonadjacent,thereby forming a first valve sinus bounded at least in part by at leasta portion of the inner conduit surface and at least a portion of thefirst sinus structure, and at least a portion of the second sinusstructure and a portion of the inner conduit surface may be nonadjacent,thereby forming a second valve sinus bounded at least in part by atleast a portion of the inner conduit surface and at least a portion ofthe second sinus structure.

In an embodiment, a method of manufacturing a hybrid tissue-engineeredvalved conduit includes providing a heart valve structure having aconduit comprising a conduit wall, an inner conduit surface, an outerconduit surface, and a diameter, and a heart valve multi-leafletstructure, forming at least one conduit breach through the conduit wall,the at least one conduit breach having two conduit breach edges,providing at least one biodegradable structure having at least twosides, affixing a first biodegradable structure side to a first conduitbreach edge, and affixing a second biodegradable structure side to asecond conduit breach edge. The heart valve multi-leaflet structure mayinclude a first heart valve leaflet, having a first sinus edge and afirst fan edge, and a second heart valve leaflet, having a second sinusedge and a second fan edge, in which the first fan edge may intersectthe second fan edge at an outer commissure point, and the first sinusedge may intersect the second sinus edge at an inner commissure point,thereby forming a commissure extending from the outer commissure pointto the inner commissure point. Additionally, the first fan edge mayintersect the first sinus edge at a first outer leaflet point, therebyforming a first baseline extending from the first outer leaflet point tothe commissure, the first baseline further having a first width asmeasured from the first outer leaflet point to the commissure. Further,the second fan edge may intersect the second sinus edge at a secondouter leaflet point, thereby forming a second baseline extending fromthe second outer leaflet point to the commissure, the second baselinefurther having a second width as measured from the second outer leafletpoint to the commissure. In addition, the second baseline may beessentially collinear with the first baseline. The first sinus edge mayalso extend from and may not be coextensive with the first baseline,thereby forming a first sinus structure bounded by the first sinus edge,the commissure, and the first baseline, and the second sinus edge mayextend from and may not be coextensive with the second baseline, therebyforming a second sinus structure bounded by the second sinus edge, thecommissure, and the second baseline. Further, the first fan edge mayextend from and may not be coextensive with the first baseline, therebyforming a first fan structure bounded by the first fan edge, thecommissure, and the first baseline, and the second fan edge may extendfrom and may not be coextensive with the second baseline, therebyforming a second fan structure bounded by the second fan edge, thecommissure, and the second baseline. Additionally, at least a portion ofthe first fan edge, at least a portion of the second fan edge, and atleast a portion of the inner conduit surface may be mutually disposed toform a valve gap. Further, at least a portion of the first sinusstructure and a portion of the inner conduit surface may be nonadjacent,thereby forming a first valve sinus bounded at least in part by at leasta portion of the inner conduit surface and at least a portion of thefirst sinus structure, and at least a portion of the second sinusstructure and a portion of the inner conduit surface may be nonadjacent,thereby forming a second valve sinus bounded at least in part by atleast a portion of the inner conduit surface and at least a portion ofthe second sinus structure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an embodiment of a heart valve leaflet structurewithin a conduit.

FIG. 2 illustrates a method of fabricating a heart valve structure inaccordance with the present disclosure.

FIG. 3A illustrates an embodiment of a heart valve leaflet structurehaving a single leaflet composed of a sinus edge having one component inaccordance with the present disclosure.

FIG. 3B illustrates an embodiment of a heart valve leaflet structurehaving a single leaflet composed of a sinus edge having multiplecomponents in accordance with the present disclosure.

FIG. 3C illustrates an embodiment of a heart valve leaflet structurehaving multiple leaflet structures each composed of a sinus edge havingone component in accordance with the present disclosure.

FIG. 3D illustrates an embodiment of a heart valve leaflet structurehaving multiple leaflets, each composed of a sinus edge having multiplecomponents in accordance with the present disclosure.

FIG. 3E illustrates an embodiment of a sinus stencil in accordance withthe present disclosure.

FIG. 4 illustrates an embodiment of a heart valve structure inaccordance with the present disclosure.

FIG. 5 illustrates an embodiment of an open and closed heart valveleaflet structure within a heart valve structure in accordance with thepresent disclosure.

FIG. 6 illustrates embodiments of devices to form one or more conduitsinuses in a heart valve structure in accordance with the presentdisclosure.

FIG. 7 is a flow chart of one embodiment of a method to provide a modelof a heart valve leaflet structure in accordance with the presentdisclosure.

FIG. 8A illustrates an embodiment of a heart valve leaflet structuremodel depicting sinus structure beams in accordance with the presentdisclosure.

FIG. 8B illustrates an embodiment of a sinus stencil model to be used insimulations with the heart valve leaflet structure model in FIG. 8A inaccordance with the present disclosure.

FIG. 8C illustrates an embodiment of a sinus structure model with sinusstructure beams pined against the inner surface of a conduit inaccordance with the present disclosure.

FIG. 8D illustrates an embodiment of a point-element aggregate meshrepresentation in accordance with the present disclosure.

FIG. 9 illustrates embodiments of a hybrid tissue-engineered heart valvestructure in accordance with the present disclosure.

DETAILED DESCRIPTION

FIG. 1 illustrates an embodiment of an artificial heart valve structure100 that may be used, in a non-limiting example, as a shunt forconnecting of the right ventricle to the pulmonary artery following aNorwood operation, as frequently performed for the treatment ofhypoplastic left heart syndrome. In one non-limiting example, theartificial heart valve structure 100 may be indicated for the correctionor reconstruction of the right ventricle outflow tract (RVOT) inpediatric patients. Such reconstruction may be indicated for congenitalheart disorders such as tetralogy of Fallot, Truncus Arterious,Dextro-Transposition of the Great Arteries, Pulmonary Atresia of IntactVentricular Septum, or Aortic Valvular Disease. Such an artificial heartvalve structure 100 may also be indicated for the replacement ofpreviously implanted homografts or valved conduits that have becomedysfunctional or insufficient. In addition, the artificial heart valvestructure 100 may have applications in treating a wider range of heartdisorders, including other areas of the heart.

In one embodiment, an artificial heart valve structure 100 may include agenerally tubular flexible conduit 110 containing a heart valve leafletstructure 130. In one embodiment, a heart valve leaflet structure 130may be a heart valve single leaflet structure. In another embodiment,the heart valve leaflet structure 130 may be a heart valve multi-leafletstructure. A conduit 110 may be characterized as having a wall with aninner conduit surface 120, an outer conduit surface, and a diameter. Inone non-limiting example, a conduit 110 may have a size less than orabout 12 mm. In another non-limiting example, a conduit 110 may have asize greater than about 12 mm. In a non-limiting example, a heart valveleaflet structure 130 may include at least one generally triangularshaped fan structure 150, and may be located along the minor curvaturealong the inner surface 120 of conduit 110. In one non-limiting example,a heart valve leaflet structure may have extensions such as “wings”along one or more sinus structures, to allow for the placement ofadditional means of connection to the conduit inner surface. A heartvalve leaflet structure 130 may have one or more sinus edges 140 fixedto the inner surface 120 of a conduit 110, and one or more fanstructures 150 that can take on either an open or closed position withrespect to the inner surface 120 of the conduit 110. In anothernon-limiting example, the one or more sinus edges 140 may have a fanshape.

In one embodiment, the conduit 110 and/or heart valve leaflet structure130 may be made from a biocompatible and hemocompatible polymer. In onenon-limiting embodiment, the polymer may be a fluoropolymer.Non-limiting examples of such biocompatible and hemocompatible polymersmay include polytetrafluoroethylene, expanded polytetrafluoroethelyne,polyester, polyethylene terephthalate, polydimethylsiloxane,polyurethane, and/or combinations of those materials. In anotherembodiment, a conduit 110 and/or heart valve leaflet structure 130 maybe made of a polymer coated with at least one bioactive coating. Instill another embodiment, a conduit 110 and/or heart valve leafletstructure 130 may be surface-modified to include a bioactive material.In one non-limiting embodiment, a bioactive coating may be ananti-coagulant coating or a surface treatment to promotebiocompatibility. Non-limiting examples of an anti-coagulant coating mayinclude a coumarin, heparin, a heparin derivative, a Factor Xainhibitor, a direct thrombin inhibitor, hementin, sintered poroustitanium microspheres, and/or combinations of those materials.

The material from which a heart valve leaflet structure 130 may befabricated may have a thickness of about 0.05 mm to about 0.2 mm. In onenon-limiting embodiment, a heart valve leaflet structure 130 may be cutout of the material by hand, or with a hand-held tool. In oneembodiment, a heart valve leaflet structure 130 may be cut out with alaser-cutter. In one embodiment, the heart valve leaflet structure 130may be produced using a 3D printer and/or similar polymer injectiondevices. In one non-limiting example, a conduit 110 may have a thicknessof about 0.5 mm to about 1 mm. In another non-limiting example, aconduit 110 may also have a diameter of about 8 mm to about 24 mm.

The sinus edge 140 of a heart valve leaflet structure 130 may be affixedto the inner surface 120 of a conduit 110. In one non-limiting example,the sinus edge 140 may be affixed by suturing. In another non-limitingexample, a sinus edge 140 may be affixed via a bonding method such aslaser welding, chemical welding, gluing, and/or suturing.

FIG. 2 illustrates an embodiment of a method 200 for fabricating anartificial heart valve structure. A flexible conduit may be provided 210including a wall having an inner surface 212 and an outer surface 215.The conduit may then be everted 220, thereby providing access to theinner surface 212. One or more heart valve leaflet structures 235 may beprovided that may be affixed 230 to the exposed inner surface 212. Inone non-limiting embodiment, illustrated in FIG. 1, a heart valveleaflet structure may comprise one heart valve single leaflet structure.Alternatively, as illustrated in FIG. 2, multiple heart valve singleleaflet structures 235 may be separately affixed to the exposed innersurface 212 of a conduit. In another alternative embodiment, a heartvalve multi-leaflet structure may be so affixed.

As disclosed above, without limitation, one or more heart valve leafletstructures 235 may be affixed to a conduit inner surface 212 bysuturing, chemical welding, heat welding, or gluing. In one non-limitingembodiment, a heart valve leaflet structure may be provided by applyinga heart valve leaflet structure stencil, having essentially the samemeasurements as the final heart valve leaflet structure, to a material.One or more marks may be made on the material to essentially follow theheart valve leaflet structure stencil. A user may use a means to cut outor extract a heart valve leaflet structure from the material based atleast in part on the markings made on the material.

In one embodiment, one or more heart valve leaflet structures 235 may bepositioned against the inner surface 212 by eye prior the heart valveleaflet structures being affixed to the inner surface. In an alternativeembodiment, a sinus stencil may be provided. A sinus stencil may be usedby a fabricator as a template for marking the inner surface 212, therebyproviding proper placement and alignment of one or more heart valveleaflet structures 235. The marking on the conduit inner surface 212 maybe substantially the same as the sinus stencil. One or more sinus edgesof one or more heart valve leaflet structures 235 may then be affixed tothe conduit along the shape marked on the inner surface 212.

In one embodiment, a sinus stencil may have identical shape, size and/ordimensions as one or more heart valve leaflet structures 235. In analternative embodiment, the sinus stencil may have a shape, size, and/ordimensions that differ from the shape, size, and/or dimensions of theone or more heart valve leaflet structures 235. Although FIG. 2illustrates affixing one or more heart valve single leaflet structuresto the inner surface 212 of the conduit, it may be appreciated thatother, more complex, heart valve leaflet structures may be similarlyaffixed.

Once the one or more heart valve leaflet structures 235, have beenaffixed to the inner surface 212 of the conduit, the conduit may bereverted 240. The final heart valve structure may thus be formed 250having the one or more heart valve leaflet structures 255 on theinterior of the conduit, and the outer surface 215 of the conduit beingdisposed at the exterior of the conduit.

A heart valve leaflet structure as illustrated in FIG. 1 may include anumber of components. FIGS. 3A and 3B illustrate two embodiments of aheart valve single leaflet structure 350. A heart valve leafletstructure may include a sinus edge 355 and a fan edge 360 that mayintersect at one or more outer leaflet points 365 a,b. In oneembodiment, a baseline 335 may be defined as a line essentially joiningthe outer leaflet points 365 a,b. In one embodiment, a baseline 335 maythus divide the heart valve leaflet structure 350 into two portions: afan structure (bounded at least by the fan edge 360 and the baseline335), and a sinus structure (bounded at least by the sinus edge 355 andthe baseline 335).

Several metrics may be applied to the heart valve leaflet structure 350.For example, a fan structure may have a fan structure height 340 asmeasured from a maximal point 370 on the fan edge 360 that is mostdistal from the baseline 335, to the baseline. It may be appreciatedthat a fan edge 360 coextensive with its respective baseline 335 mayhave effectively no fan structure height 340. Therefore, an embodimentof a heart valve leaflet structure having a fan structure may have atleast a portion of the fan edge 360 non-coextensive with the baseline335. A sinus structure may also have a height 320 measured from amaximal point 375 on the sinus edge 355 most distal from the baseline335, to the baseline. It may further be appreciated that a sinus edge355 coextensive with its respective baseline 335 may have effectively noheight 320. Therefore, an embodiment of a heart valve leaflet structurehaving a sinus structure may have at least a portion of the sinus edge355 non-coextensive with the baseline 335. The baseline 335 may alsohave a width as measured between the outer leaflet points 365 a,b.

It may be appreciated that either one or both of the sinus edge 355and/or the fan edge 360 may be composed of multiple components. Forexample, as illustrated in FIG. 3B, a sinus edge 355 may be composed ofseveral components 355 a-f. In some non-limiting examples, thecomponents may be essentially straight lines, such as 355 a,c,d,f. Insome other non-limiting examples, sinus edge components may have morecomplex shapes such as “wings” 355 b and 355 e in FIG. 3B. It may alsobe appreciated that the maximal point of a sinus edge 375 may occur atthe intersection of two sinus edge components (for example, theintersection of 355 c and 355 d), which may conveniently be termed a“sinus intersection”.

It may be appreciated that a heart valve leaflet structure may becomposed of a number of leaflets. FIG. 3C illustrates one non-limitingexample of a heart valve multi-leaflet structure composed of two heartvalve leaflets, 350 a,b. Many of the components in FIG. 3C may be foundin FIGS. 3A and 3B. Thus there may be two sinus edges (375 a,b), two fanedges (360 a,b), two fan maximal points (370 a,b), each defining a fanheight (340 a,b), and two sinus maximal points (375 a,b), each defininga height (320 a,b).

In addition, the two leaflets (350 a,b) may be joined at theirrespective edges. Thus, the two fan edges (360 a,b) may intersect at apoint 390 that may be termed an outer commissure point, and the twosinus edges (355 a,b) may intersect at a point 395 that may be termed aninner commissure point. A commissure 330 may thus be defined as astructure effectively bounded at least by the inner commissure point 395and the outer commissure point 390. The commissure 330 may becharacterized by a commissure length. An embodiment of a two-leafletheart valve structure illustrated in FIG. 3C may be considered to havetwo baselines (335 a,b), one baseline associated with each respectiveleaflet (350 a,b). Each baseline (335 a,b) may be characterized by awidth as measured from an outer leaflet point (365 a,b) to thecommissure, 330. The two baselines 335 a,b may also be essentiallycollinear. As disclosed above, with respect to the embodimentillustrated in FIG. 3A, a fan structure may be that portion of theleaflet 350 bounded at least by a fan edge 360 and a baseline 335. Itmay be appreciated that a fan structure of either one or both heartvalve leaflets 350 a,b in a two-leaflet heart valve structure may alsobe bounded at least by a portion of a commissure 330 in addition to therespective fan edges (360 a,b) and baselines (335 a,b). Similarly, itmay be appreciated that a sinus structure of either or both heart valveleaflets 350 a,b in a two-leaflet heart valve structure may be boundedat least by a portion of a commissure 330 in addition to the respectivesinus edges (375 a,b) and baselines (335 a,b).

It may also be appreciated that a heart valve multi-leaflet structuremay not necessarily include all the features as disclosed above withrespect to FIG. 3C. In one non-limiting alternative embodiment, a heartvalve multi-leaflet structure may have a commissure 330 essentiallylacking a length. In such an embodiment, the inner commissure 395 pointmay essentially be coextensive with the outer commissure point 390.

It may be understood, with reference to the method illustrated in FIG.2, that one or more sinus edges 355 a,b of the one or more heart valveleaflets 350 a,b may serve as at least a portion of points of attachmentbetween the heart valve leaflets and the inner surface of a conduit. Itmay also be appreciated that at least a portion of a commissure 330 mayalso be affixed to the inner surface of a conduit.

Although FIGS. 3A-C illustrate embodiments of heart valve leafletstructures composed of one or two leaflets, it is understood that aheart valve leaflet structure may be composed of any number of leaflets.For example, a heart valve three-leaflet or four-leaflet structure mayalso be considered. By extension of the heart valve leaflet structureillustrated in FIG. 3C, a heart valve three-leaflet structure maycomprise three leaflets, each leaflet having one or more of a sinusedge, a sinus structure, a fan edge, a fan structure, a baseline, aheight, and a fan structure height. Such a three-leaflet structure mayinclude, in one embodiment, two commissures: one commissure between afirst leaflet and a second leaflet, and a second commissure between thesecond leaflet and a third leaflet. Each commissure may have acommissure length. Outer and inner commissure points equivalent to 390and 395, respectively, may be also be defined between each pair ofadjacent leaflets.

It may be further appreciated that equivalent metrics describing eachleaflet of a multi-leaflet heart valve leaflet structure may differ. Inone non-limiting embodiment, one leaflet may have a height that maydiffer from the height of any one or more other leaflets composing themulti-leaflet heart valve leaflet structure. In another non-limitingembodiment, one leaflet may have a sinus edge having a differentperimeter length than the sinus edge perimeter length of one or moreother leaflets. In yet another non-limiting embodiment, the sinus edgeshape of one leaflet may differ from the sinus edge shape of one or moreother leaflets. In still another non-limiting example, a fan structureshape of one leaflet may differ from the fan structure shape of one ormore other leaflets.

Alternatively, some leaflets may have equivalent metrics that have aboutthe same metric values. Thus, in one non-limiting example, some or allof the leaflets in a multi-leaflet heart valve leaflet structure mayhave baselines having about the same width. In another one non-limitingexample, some or all of the leaflets in a multi-leaflet heart valveleaflet structure may have heights having about the same length.

Another embodiment of a heart valve multi-leaflet structure 300 isillustrated in FIG. 3D. A heart valve multi-leaflet structure 300 mayinclude a pair of heart valve leaflets, each having an essentiallytriangular sinus structure 302 a and 302 b. A sinus edge of each leafletmay be composed of a combination of two or more components, including,as non-limiting examples, an outer edge component (305 a,b) plus arespective inner edge component (310 a,b). In addition, each heart valveleaflet may have a fan structure 315 a and 315 b. One end of a fan edgemay intersect an end of its respective outer edge component, 305 a,b, toform an outer leaflet point, 365 a,b. In addition, the fan edge of oneleaflet may intersect the fan edge of the second leaflet at an outercommissure point 390. Further the sinus edge of one leaflet mayintersect the sinus edge of the second leaflet at an inner commissurepoint 395. With respect to the embodiment illustrated in FIG. 3D, aninner commissure point 395 may be found at an intersection of the firstinner edge component 310 a and the second inner edge component 310 b. Asdisclosed above with respect to FIG. 3C, a commissure 330 may be definedas the portion bounded at least by the outer commissure point 390 andthe inner commissure point 395.

As disclosed above with respect to FIG. 3C, each leaflet may have abaseline 335 a,b, having a width measured between the respectivebaseline outer leaflet point 365 a,b and a commissure 330. Further, eachinner edge component 310 a and 310 b and each outer edge component 305 aand 305 b may be characterized by a length. Each leaflet may also have asinus intersection (375 a,b) located essentially at the intersectionbetween an inner edge component (310 a,b) and the respective outer edgecomponent (305 a,b). Additionally, each sinus structure may becharacterized as having a height, 320 a and 320 b, measured from therespective base (335 a,b) to the respective sinus intersection (375a,b). It may be appreciated that the sinus intersection of each leaflet(375 a,b) may also be the maximal point on the respective sinus edgethat is most distal from the respective baseline (335 a,b).

It may be appreciated that metrics associated with one heart valveleaflet may be independent of another. Thus, the length of leaflet inneredge component 310 a may differ from the length of inner edge component310 b; the length of outer edge component 305 a may differ from thelength of outer edge component 305 b; height 320 a may differ fromheight 320 b; the width of baseline 335 a may differ from the width ofbaseline 335 b; and fan structure height 340 a may differ from fanstructure height 340 b. Alternatively, in one non-limiting embodiment,the length of inner edge component 310 a may be substantially the sameas the length of inner edge component 310 b. In another non-limitingembodiment, the length of outer edge component 305 a may besubstantially the same as the length of out edge component 305 b Inanother non-limiting embodiment, height 320 a may be substantially thesame as height 320 b. In yet another non-limiting embodiment, the widthof baseline 335 a may be substantially the same as the width of baseline335 b. In still another non-limiting embodiment, fan structure height340 a may be substantially the same as fan structure height 340 b.

The metrics associated with a heart valve leaflet structure may bescaled with respect to each other. In one non-limiting example, theratio between the height of one leaflet, such as 320 a (or 320 b), andthe width of the baseline of that leaflet, such as 335 a (or 335 b,respectively), may be about 0.41 to about 0.77. In another non-limitingexample, the ratio between the inner edge component length of oneleaflet, such as 310 a (or 310 b), and the width of the baseline of thatleaflet, such as 335 a (or 335 b, respectively), may be about 0.44 toabout 0.77. In still another non-limiting example, the ratio between alength of the commissure 330 and the width of the base of one leaflet,such as 335 a (or 335 b), may be about 0.18 to about 0.38. In addition,metrics associated with a heart valve leaflet structure may be scaledwith respect to a metric associated with a conduit to which it may beaffixed. In one non-limiting example, the ratio between the width of thebaseline of a leaflet, such as 335 a or 335 b, and the diameter of theconduit may be of about 0.054 to about 0.17.

While the sinus structure 302 a,b of a heart valve leaflet asillustrated in FIG. 3D may be of a generally triangular shape, it may beappreciated that the sinus structure may also encompass alternativeshapes. Thus, embodiments of the sinus structure 302 a,b may include,without limitation, a generally quadrilateral shape, any closedmulti-lateral shape, curved shapes, oval shapes, or other geometricshapes that may provide a sinus edge having one or more components thatmay be affixed to the inner surface of a conduit.

Each fan structure 315 a and 315 b may have any type of angular, linear,or curved fan edge. In one non-limiting example, each fan structure, 315a and 315 b, may have a lobular edge, each lobular fan structurecharacterized by a fan structure height, 340 a and 340 b, measured fromthe maximal point of each fan edge to its respective base, 335 a and 335b. In one non-limiting embodiment, a fan structure, 315 a or 315 b, maybe essentially bilaterally symmetric. In another embodiment, fanstructure 315 a or 315 b may be asymmetric and have an lobular edgecomposed of a steep portion proximate to an outer edge component (suchas 305 a or 305 b) of the sinus edge of its respective heartvalveleaflet (350 a or 350 b), and a shallow portion proximate to theouter commissure point 390. In another embodiment, fan structure 315 aof one leaflet may be essentially mirror-image symmetric to fanstructure 315 b with respect to the commissure. In another embodiment,fan structure 315 a may be essentially identical to fan structure 315 b.In yet another embodiment, fan structure 315 a may differ from fanstructure 315 b in edge shape, edge perimeter length, fan structurearea, or in other metrics.

The dimensions of a fan structure, 315 a and 315 b, may be scaled withrespect to other dimensions of a heart valve multi-leaflet structure. Inone non-limiting example, the ratio between a fan structure height ofone valve leaflet, such as 340 a (or 340 b), and the width of thebaseline of that leaflet, such as 335 a (or 335 b, respectively), may beabout 0.07 to about 0.14. While a fan structure, as disclosed above, mayinclude an asymmetric single lobe disposed towards the outer edgecomponent (305 a,b) of the heart valve multi-leaflet structure, it maybe appreciated that such a structure may be a non-limiting embodiment ofa fan structure. Alternative fan structures may include one or morelobes, angles, and/or other geometries. Additional features may includesymmetric or asymmetric distributions of such lobular, angular, orlinear fan structures, which may appear along any one or more portionsalong a baseline.

As disclosed above, with respect to FIG. 2, a heart valve leafletstructure may be positioned on the inner surface 212 of an evertedconduit by using a marking on the inner surface having a shapeessentially similar to a sinus stencil. FIG. 3E illustrates anembodiment a sinus stencil 300′ that may be used in conjunction with theheart valve multi-leaflet structure 300 illustrated in FIG. 3D. In oneembodiment, a sinus stencil 300′ may have the shape of two conjoinedessentially triangular portions having coextensive bases, similar to theconjoined sinus structures 302 a,b illustrated in FIG. 3D. In anembodiment, a sinus stencil 300′ may lack one or more fan structures. Inan alternative embodiment, a sinus stencil 300′ may include one or morefan structures or portions of fan structures. In one non-limitingexample, a sinus stencil 300′ may include, for each sinus structure (302a and 302 b), a sinus stencil outer edge component (305 a′ and 305 b′),a sinus stencil inner edge component (310 a′ and 310 b′), and a sinusstencil baseline (335 a′ and 335 b′). Sinus stencil inner edgecomponents, 310 a′ and 310 b′, may intersect essentially at the sinusstencil collinear bases (335 a′ and 335 b′). Alternatively, sinusstencil inner edge components 310 a′ and 310 b′ may intersect at somepoint away from the collinear sinus stencil baselines, 335 a′ and 335b′, thereby forming a sinus stencil commissure 330′. Each sinus stencilouter edge component (305 a′ and 305 b′) and inner edge component (310a′ and 310 b′) may be characterized by a respective length. Further,each sinus stencil may be characterized by one or more heights (320 a′and 320 b′). Additionally, each sinus stencil baseline (335 a′ and 335b′) may be characterized by a respective width. The sinus stencilcommissure 330′ may also be characterized by a sinus stencil commissurelength.

It may be appreciated that metrics associated with a sinus stencil 300′may be about the same as or differ from the respective equivalentmetrics associated with a heart valve leaflet structure 300. It may beunderstood that “respective equivalent metrics” may refer tomeasurements of equivalent components of a heart valve multi-leafletstructure 300 and a sinus stencil 300′. Thus a heart valve leafletstructure outer edge component 305 b (or 305 a) may be an equivalentcomponent to a sinus stencil outer edge component 305 b′ (or 305 a′,respectively). A heart valve leaflet structure inner edge component 310b (or 310 a) may be an equivalent component to a sinus stencil inneredge component 310 b′ (or 310 a′, respectively). A heart valve leafletstructure height 320 b (or 320 a) may be an equivalent component to asinus stencil height 320 b′ (or 320 a′, respectively). A heart valveleaflet structure baseline 335 b (or 335 a) may be an equivalentcomponent to a sinus stencil baseline 335 b′ (or 335 a′, respectively).A heart valve leaflet structure commissure 330 may be an equivalentcomponent to a sinus stencil commissure 330′.

Although FIG. 3E illustrates a sinus stencil 300′ having two sinusstructures 302 a′ and 302 b′, it may be appreciated that a sinus stencilmay be composed of any number of sinus structures. It may be appreciatedthat the number of sinus structures, 302 a′ and 302 b′, of a sinusstencil 300′ may correspond to the number heart valve leaflets 350 a,bof a heart valve leaflet structure 300 with which it may be used. Aheart valve leaflet structure 300 composed of a single or multipleleaflets (for example three leaflets) may have an equivalent sinusstencil 300′ composed of the same number of sinus structures. Thus, aheart valve leaflet structure 300 having a single leaflet may have anequivalent sinus stencil 300′ having a single sinus structure, while aheart valve leaflet structure having three leaflets (as a non-limitingexample) may have an equivalent sinus stencil having three sinusstructures.

Once a heart valve multi-leaflet structure has been properly positionedon the inner surface of an everted conduit, the heart valvemulti-leaflet structure may be affixed to the conduit as disclosed abovein FIG. 2, 230. In one non-limiting embodiment, a heart valvemulti-leaflet structure may be affixed to a conduit along at least aportion of the sinus edge. In the embodiment illustrated in FIG. 3D, aportion of the sinus edge may include any portion or portions along thecombination of the outer edge component 305 a (or 305 b) plus inner edgecomponent 310 a (or 310 b) of the respective leaflets. In anotherembodiment, a heart valve multi-leaflet structure may also be affixed tothe inner surface at least along a portion of the commissure 330. Once aheart valve multi-leaflet structure has been properly affixed to theinner surface of the conduit, the conduit may be reverted, (FIG. 2,240).

As disclosed above, any one or more of the metrics associated with asinus stencil 300′ may be about the same as or differ from therespective equivalent metrics of a heart valve multi-leaflet structure300. In one non-limiting embodiment, the metrics associated with a heartvalve multi-leaflet structure 300 may be about the same as therespective equivalent metrics associated with the sinus stencil 300′.For such an embodiment, it may be appreciated that sinus structures 302a and 302 b may be lying essentially against and effectively contactingthe inner surface of the conduit.

In another non-limiting embodiment, one or more metrics associated witha heart valve single leaflet or multi-leaflet structure 300 may belarger than the respective equivalent metrics associated with a sinusstencil 300′. As one non-limiting example, an inner edge component of aheart valve multi-leaflet structure (310 a, for example) may have alength of about 8.1 mm, while the length of the equivalent inner edgecomponent of the sinus stencil (310 a′, for example) may be about 7.7mm. For such an embodiment, it may be appreciated that at least aportion of sinus structures 302 a and 302 b may be nonadjacent to theinner surface of a conduit. Thus, some portion of sinus structures 302 aand 302 b may be unattached to and have no or minimal contact with aconduit inner surface; however, some other portion of the sinusstructures may be directly attached to and in effective contact with aconduit inner surface. The portion of sinus structures 302 a and 302 bthat may be directly attached to and be in contact with a conduit innersurface may include at least some portion of the sinus edges. At leastsome portion of sinus structures 302 a and 302 b may be puckered awayfrom the inner surface of a conduit when a heart valve multi-leafletstructure is affixed to the inner surface of the conduit. This puckeringeffect may thereby produce a valve sinus bounded by at least someportion of a sinus structure (302 a or 302 b) and at least a portion ofthe inner surface of the conduit. Depending on the orientation of fanstructures 315 a,b with respect to the inner surface of a conduit, avalve sinus may also be in part bounded by at least a portion of fanstructures 315 a,b and/or baselines 335 a,b.

FIG. 4 illustrates an interior downstream view of a heart valvestructure in an open, 440, and closed, 450, configuration. In an open440 configuration, blood may flow through the heart valve multi-leafletstructure, forcing fan structures 415 a and 415 b towards the innersurface of a conduit. In a closed configuration 450 fan structures 415a′ and 415 b′ may form a closure against fluid backflow. In somenon-limiting examples, lobes of fan structures 415 a′ and 415 b′ may beproximate, juxtaposed, and/or overlap in whole or in part. In somenon-limiting examples, the closure may be planar, concave, and/orconvex, or form an otherwise non-planar surface.

Closed configuration 450 further illustrates the relative locations ofsutures or other means of affixing a heart valve multi-leaflet structureto the inner surface of a conduit. Specifically, inner edge componentsof two leaflet structures may be affixed as indicated by 410, whileouter edge components of the two leaflet structures may be affixed asindicated by 405 a and 405 b. In one embodiment, a heart valvemulti-leaflet structure and at least a portion of a conduit innersurface may be disposed to form a small gap 460 bounded by at least aportion of the inner surface of the conduit and a portion of the fanedge of each of fan structures. For a heart valve multi-leafletstructure in FIG. 4 corresponding to the embodiment of a heart valvemulti-leaflet structure 300 in FIG. 3D, gap 460 may be bounded by thesteep edges of fan structures 315 a,b and the inner surface of aconduit. It may be understood that alternative heart valve multi-leafletstructures may include fan structures having fan edges with shapesdiffering from those disclosed above with respect to FIG. 3D. However,at least some portion of the fan edge of each such fan structure, whenin closed configuration 450, may also form a gap 460 with the innerconduit surface.

Although FIG. 4 illustrates a heart valve structure having two leaflets,it may be appreciated that a heart valve structure may include anynumber of leaflets. Thus, a heart valve structure may incorporate asingle leaflet, as illustrated in FIG. 1. Alternatively, a heart valvestructure may incorporate a heart valve leaflet structure composed ofthree of more leaflets. In a non-limiting example, a heart valvestructure may have three leaflets, the third leaflet positioned to covergap 460 so as to essentially prevent regurgitative flow through theheart valve structure.

FIG. 5 illustrates another embodiment of a heart valve structure. Thetop view 500 presents a partial cut-away view of a heart valve structureat a portion slightly downstream of the heart valve multi-leafletstructure (shown in a closed configuration). The upstream end 502 of aheart valve structure may be positioned in a patient's vasculature orcardiac structure to receive blood flowing to the heart valve structure.The closure of a heart valve structure may be formed from two fanstructures 515 a and 515 b from a heart valve multi-leaflet structure.The closure may not be entirely closed to blood flow. In one embodiment,a small gap 560 may be formed by the mutual disposition of at least someportion of the fan edge of each of fan structures 515 a and/or 515 b andthe inner surface of a conduit. In one non-limiting example, gap 560 mayinclude about 15% of the circumference of a conduit inner surface.

Additional structures may also be present. In one embodiment, one ormore conduit sinus structures 575 a and 575 b may also be present.Conduit sinus structures 575 a and 575 b may be formed by deformation ofthe conduit wall, and may be placed downstream of a heart valvemulti-leaflet structure. Conduit sinus structures 575 a and 575 b may begenerally concave with respect to the inner surface of the conduit. Inone non-limiting example, conduit sinus structures 575 a and 575 b maybe generally spheroidally concave. In another non-limiting example,conduit sinus structures 575 a and 575 b may be generally cubicallyconcave. It may be understood that the outline and cross section ofconduit sinus structures 575 a and 575 b may have any geometry as longas the conduit sinus structures maintain a concavity with respect to aconduit inner surface.

View 540 presents an embodiment of a heart valve structure in an openconfiguration, and 550 presents an embodiment of a heart valve structurein a closed configuration. In open configuration 540, fan structures 515a′ and 515 b′ may be disposed in an extended downstream-pointingposition. An interior concavity of each of the conduit sinus structures575 a′ and 575 b′ may also be observed. In one embodiment, fanstructures 515 a′ and 515 b′ while in the open configuration 540 mayalso extend into at least a portion of the conduit sinus structures 575a′ and 575 b′. In closed configuration 550, each fan structure (forexample, 515 a″) of the heart valve multi-leaflet structure may bedisposed in a neutral position In a neutral position, the two fanstructures may be disposed with respect to each other as to form anearly complete closure. In closed configuration 550, a small gap 560′may develop from the disposition of at least a portion of the fan edges(for example, the steep edge of each fan structure) and a conduit innersurface.

While FIG. 5 illustrates an embodiment of a two-leaflet heart valvestructure, it may be appreciated that a heart valve structure mayinclude additional heart valve leaflets. In one non-limiting example, athree-leaflet heart valve structure may be considered. Such a heartvalve structure may incorporate a closure formed by the juxtaposition,proximity, and/or overlap of three fan structures. The mutualdisposition of some portions of three fan edges along with the innersurface of the conduit may result in a gap structure similar to 560′.Alternatively, three fan structures may be disposed so that,effectively, no gap is formed.

One or more conduit sinus structures 575 a and 575 b may be formed froma conduit wall according to any method appropriate for deforming theconduit wall material. FIG. 6 illustrates non-limiting examples ofconduit sinus fabrication devices 610 a and 610 b that may be used toform such conduit sinus structures. Examples of conduit wall deformationmethods may include, without limitation, one or more of mechanicaldeformation (such as stretching or mechanical forming), heat forming,and/or vacuum forming. In one example, conduit sinus structuregeometries may be created by a conduit sinus fabrication device 610 ahaving a dome 650 that may have the shape of the desired conduit sinusgeometry. A conduit sinus fabrication device 610 a may deform theconduit material from the inside of a conduit via applied pressureand/or heat. Additionally, the portion of the conduit away from thedomed portion 650 may be preserved by a semi-cylindrical mechanicalstabilizer 625, or a cylindrical stabilizer 620 a,b having componentslocated inside and outside of a conduit. In one embodiment, a stabilizer625 may contain an opening to allow the dome 650 and deformed conduitwall material to move while preventing movement of the conduit wall awayfrom a conduit sinus structure. In one embodiment, an inner 620 bstabilizer and an outer 620 a stabilizer may be aligned manually bymeans of attachment to a conduit sinus fabrication device 610 a and 610b. In another non-limiting embodiment, a conduit sinus fabricationdevice 610 a and 610 b may include magnets to help stabilize the conduitwall material. Non-limiting examples of a conduit sinus fabricationdevices 610 a and 610 b may have the dome 650 actuated manually, by apotential energy device (such as a spring), or bymagnets/electromagnets. In another non-limiting example, the dome 650may be constructed from a thermally conductive material and heated byelectric heating device 640 contained within the dome itself.

The shape and/or metrics associated with a heart valve multi-leafletstructure may be determined by a health care provider based on his orher experience and/or expertise. In an alternative embodiment, the shapeand/or metrics associated with a heart valve leaflet structure may bedetermined, at least in part, based on calculations including, withoutlimitation, mathematical modeling and/or optimization methods. In onenon-limiting embodiment, customized heart valve leaflet structures maybe fabricated for an individual patient. In another non-limitingembodiment, a ‘standardized” heart valve leaflet structure may befabricated that may be used by a number of patients who may not requirea completely customized heart valve structure as a remedy for apathology.

In one embodiment, modeling and/or optimization calculations may be usedto reduce diastolic flow regurgitation through a heart valve structure,as well as to improve effective orifice area and overall heart valvestructure function. In one non-limiting embodiment, a heart valveleaflet structure modeling program may predictively generate one or moreheart valve leaflet structure models based at least on geometricparameters and solid-mechanics principals. In another non-limitingembodiment, one or more solid heart valve leaflet structure models maybe analyzed according to one or more fluid flow analytical methods.Non-limiting examples of such fluid flow analytical methods may includefluid-structure interaction (FSI) and computational fluid dynamics (CFD)simulations. In a non-limiting embodiment, an iterative optimizationmethod for generating heart valve leaflet structure models may include:(1) calculating a heart valve leaflet structure model based on a set ofparameters including one or more geometric parameters; (2) analyzing aperformance of the heart valve leaflet structure model based at least inpart on one or more fluid flow analytical methods; (3) calculating aperformance cost function according to data calculated by the one ormore fluid flow analytical methods; and (4) varying one or more of theheart valve leaflet structure modeling parameters in a manner tominimize the value of the valve performance cost function.

Mathematical modeling and/or optimization calculations that may be usedto calculate shapes and/or dimensions of heart valve leaflet structuresmay include, without limitation, computational fluid dynamics (CFD),solid-mechanics modeling, fluid/structure interaction (FSI) modeling,and blood-flow optimization algorithms Calculations based on CFD modelsmay show a difference in blood flow velocity based on a curvature of theconduit component of a heart valve structure. For example, a blood flowmodel may indicate greater flow along a conduit axis having a smallradius of curvature as opposed to the blood flow in a conduit having alarger radius of curvature. CFD models, for example, may provide data tosuggest that a curved conduit should not have a heart valve leafletstructure at the conduit bottom as a heart valve leaflet structure lowerleaflet may become stuck at the closing phase, thereby leading tothrombosis.

Mathematical calculations and/or optimization calculations may becarried out, for example, by means of one or more computing devices.Such computing devices may include, without limitation, one or more ofthe following: central processor units, numerical accelerators, staticand/or dynamic memories, data storage devices, data input devices, dataoutput devices, communication interfaces, and visual displays. While asingle computing device may be used for such calculations, multiplecomputing devices, for example in a shared network or cloudconfiguration, may also be used. It may be appreciated that the one ormore computing devices may operate independently or in concert. Inaddition, communications between one or more users and one or morecomputing devices may occur over one or more input interface device,including, without limitation, a keyboard, a mouse, a track-ball, astylus, a voice recognition system, and/or a touch pad display. Inaddition, the one or more computing devices may provide outputinformation to the one or more users by one or more output interfacedevice, including, without limitation, a visual display, a printer,and/or an audio interface. Data communication between computing devicesmay occur over one or more computing system communication interface,including, but not limited to, a serial interface, a parallel interface,an Ethernet interface, a wireless interface, and/or an opticalinterface. Additional communications between computing devices, orbetween computing devices and users, may be accomplished over one ormore computing system communication protocols including, but not limitedto, a personal area networks (such as BlueTooth), a local area network,a wide area network, and/or a satellite network.

FIG. 7 is a flow chart illustrating an embodiment of a method fordesigning a heart valve leaflet structure.

Initially, leaflet modeling parameters may be provided to the heartvalve leaflet structure model 700. Non-limiting examples of leafletmodeling parameters may include one or more of a sinus edge shape, asinus edge perimeter length, a fan edge shape, a fan edge perimeterlength, a height, a fan structure height, a baseline width, a commissurelength, a modulus of elasticity of the heart valve leaflet structurematerial, a pressure across the heart valve leaflet structure, and afluid flow rate through the heart valve leaflet structure. A leafletstructure modeling computation may then create initial two dimensionalleaflet shapes.

Data provided to such leaflet structure modeling computation andoptimization calculations, for example, may be used by such models andoptimization calculations to calculate patient specific shapes anddimensions of heart valve leaflet structures and/or their related sinusstencils. In one embodiment, data used in the modeling and/or optimizingcomputer programs may include, without limitation, at least somephysiological and/or anatomic data from a specific patient to receive aheart valve leaflet structure (as a customized device). In anotherembodiment, physiological and/or anatomical data from a number ofindividuals may be used either as aggregated raw data or asstatistically analyzed data (e.g. mean values, variance values, and/orstandard deviations) in modeling calculations for heart valve leafletstructures. In an embodiment, data may be derived from individualssharing at least one characteristic with a patient, including withoutlimitation, age, sex, height, weight, blood pressure, and degree ofpathology (if any).

Sinus edges and sinus structures of a heart valve leaflet structureinitial model may then be mapped onto the inner surface of a conduitmodel 705. A sinus stencil model may be used to map the sinus edge ofthe heart valve leaflet structure initial model onto the inner surfaceof a conduit model. Points composing the sinus edge may act as points ofattachment to the inner surface of a conduit model; for convenience,such an attachment may be referred to as a “pinned” attachment. For thepurpose of modeling a heart valve leaflet structure within a conduit,the flexibility of the sinus edge at the sinus edge points may result innegligible transferable moment from the pinned attachments through thesinus structure. In one embodiment of a mapping step, a heart valveleaflet structure model, including the sinus structures, may be assumedto be bilaterally symmetric with respect to a commissure.

The sinus structures may be sectioned into a finite number of thin,neighboring sinus structure beams 710. In one non-limiting embodiment,sinus structure beams may be created after the heart valve leafletstructure model has been mapped to the inner surface of a conduit model.In an alternative embodiment, sinus structure beams may be created aspart of a heart valve leaflet structure initial model. The general shapeof each beam (as a thin ribbon) may then be calculated 715. In onenon-limiting embodiment, a mode of sinus structure beam deformation maybe by buckling. A length of each sinus structure beam may be very longcompared to its end-point-to-end-point distance after being affixed tothe inner surface of a conduit. The very thin (0.1 mm) and flexiblesinus structure beams may buckle easily and may not hold significantcompressive strain. Strain between neighboring sinus structure beams mayoccur along the shape of the sinus structure. In one non-limitingembodiment, shape deformation between neighboring sinus structure beamsmay be ignored during modeling. In another non-limiting embodiment of aheart valve leaflet structure model, strain due to the weight of theheart valve leaflets may be neglected. As a non-limiting example, for aheart valve leaflet structure model based on a heart valve leafletstructure composed of expanded PTFE, the thin leaflets may have a verylow weight compared to their elastic modulus, and therefore any straininduced by the weight of the leaflets may be ignored.

In one non-limiting example, a calculation may be performed according toa numerical multi-mode buckling analysis. Each sinus structure beam mayundergo multiple interactions, both with the opposing leaflet and withthe conduit inner surface. Many possible modes of buckling may beaccounted for, both in-line and offset, including fixed-fixed (i.e. fromone unattached sinus structure edge to another unattached sinusstructure edge), pinned-pinned (i.e. from one sinus structure edgeaffixed to the conduit inner surface to another sinus structure edgeaffixed to the conduit inner surface), and pinned-fixed. In onenon-limiting embodiment, these modes of buckling may be solvednumerically. In a non-limiting embodiment, a multi-mode numericalbuckling solver may be used.

A general solution to a beam undergoing buckling may be shown to be:

y=A sin(kx)+B cos(kx)+Cx+D  (Eq. 1)

where y may be the perpendicular distance from the original sinusstructure beam at any given point. By finding the first and secondderivatives of Eq. 1, the slope and moment may be shown to be:

y′=Ak cos(kx)−Bk sin(kx)+C  (Eq. 2)

y″=−Ak ² sin(kx)−Bk ² cos(kx)  (Eq. 3)

at every point along the sinus structure beam. By imposing boundaryconditions (such as y_(o)″=y_(L)″=0 for a pinned-pinned sinus structurebeam), and maintaining sinus structure beam length and overallcontinuity, a shape of the buckled sinus structure beam may becalculated. By maintaining continuity of the distance from a given pointalong a sinus structure beam to a fixed sinus edge before and afterbuckling, a three dimensional shape of the sinus structure beam may befound after buckling.

Where a solved sinus structure beam shape intersects a solid boundary,the intersection point may be assumed to be a vertex, so that segmentsbefore and after that vertex may undergo independent buckling whilemaintaining continuity between the two segments at the intersectionpoint. This vertex point may then be iteratively varied along theboundary through an optimization routine. In one non-limitingembodiment, an optimization routine may include a vertex point costfunction defined as the discrepancy at a vertex between an appliedmoment from a sinus structure beam side and an applied moment from asolid boundary side. Under an optimization condition, a discrepancybetween the applied moments may approach about zero, since continuitymay require that applied moments may be about equal. By iterativelyapplying this procedure for all intersections that arise, a final shapeof each sinus structure beam may be calculated. In one non-limitingembodiment, the calculations may be simplified by assuming that sinusstructure beam shapes at the symmetry line between heart valve leafletsmay be linear. Results of modeling the sinus structures may includelocations of the sinus structure edge pinned to the inner surface of aconduit model, and location of the baseline of the modeled sinusstructure.

After a general shape of each beam has been calculated, each sinusstructure beam may be further sectioned into a finite number ofpoint-elements 720. A position of each of the sinus structure beam pointelements may then be calculated 715. One or more position metrics foreach sinus structure beam point-element may be calculated in accordanceto a number of different methods. In one non-limiting example, a sinusstructure beam point-element location may be calculated based at leastin part on a change in its position along the sinus structure beam fromits position along the initial sinus structure beam length. In anotherexample, a distance may be calculated between individual sinus structurebeam point-elements. In yet another example, a distance of each sinusstructure beam point-element may be calculated from the maximal point ofthe relevant sinus edge or sinus intersection. In another example, asinus structure beam point-element location may be adjusted to accountfor small amounts of strain in the leaflets.

After sinus structure beam point-element locations have been calculated,as disclosed above, each leaflet fan structure may be similarly modeled.A fan structure may initially have its baseline mapped to the baselineof its respective modeled sinus structure. In one non-limitingembodiment, a fan structure may be sectioned into a number of fanstructure beams 730. In one embodiment, the fan structure beams may becreated after the fan structure baseline has been mapped onto themodeled sinus structure baseline. In another embodiment, the fanstructure beams may be created as part of a heart valve leafletstructure initial model. A general shape of each fan structure beam maythen be calculated 735 according to modeling and optimizationscalculations as substantially disclosed above with reference to thesinus structure beams. Thereafter, each fan structure beam may besectioned into a number of fan structure beam point-elements 740, andone or more position of each fan structure beam point-element may becalculated in a manner substantially disclosed above 745 with respect tothe sinus structure beam point-elements.

After the location of sinus structure beam point-elements and fanstructure beam point-elements have been calculated, both sets ofpoint-elements may be incorporated into a single set that mayconveniently termed a “point-element aggregate”. Point-elementscomposing the point-element aggregate may then be modeled by apoint-element aggregate mesh representation 750. The point-elementaggregate mesh representation may then be smoothed 755. In onenon-limiting embodiment, the smoothing calculation may be derived fromthe use of Bezier curves.

Once a point-element aggregate mesh representation has been calculated,a solid model may be generated from the mesh model 760, incorporating athickness based upon the heart valve leaflet structure material.

FIGS. 8A and 8B illustrate non-limiting examples of results that may beobtained from an embodiment of a leaflet structure modeling computationas disclosed above. FIG. 8A illustrates a model 800 of a heart valveleaflet structure having a pair of leaflets. Sinus edges 805 a,b and 810a,b are illustrated. Two sinus structures, 802 a and 802 b areillustrated having sinus structure beams (such as 810) dividing thesinus structures. FIG. 8B illustrates a sinus stencil 800′ that may beused for mapping the heart valve leaflet structure 800 onto the innersurface of a conduit. FIG. 8C illustrates an embodiment of anon-limiting example of a result of mapping sinus edges 805 a,b and 810a,b onto the inner surface of a conduit model 840. It may be appreciatedthat sinus structure beams 810 may form a complex two dimensionalstructure. FIG. 8D illustrates a non-limiting example of a point-elementaggregate mesh representation 870 that may result from heart valveleaflet structure modeling. Intersections 880 of the mesh may representthe locations of member point of a point-element aggregate.

After a solid model of the leaflets has been generated, a performance ofthe heart valve leaflet structure model may be assessed according to oneor more fluid flow analytical calculations. In some non-limitingembodiments, fluid flow analytical methods may include CFD and FSIanalyses. Fluid flow analytical methods may be used to assess theperformance of the heart valve leaflet structure model. Fluid flowparameters that may be entered as part of the fluid flow analyticalmethods may include, without limitation, one or more of cardiac andvascular geometry, patient blood flow parameters, size and/or weight ofthe patient, size/curvature of the conduit, a cardiac output of apatient's heart, and patient blood pressure. In one non-limitingexample, fluid flow parameters associated with a patient may be acquiredby direct quantitative and qualitative measurement of the patient. Inanother non-limiting example, average values or reference values of suchfluid flow parameters may be acquired from clinical literature or othercomputational simulations. Fluid flow parameters may then be used in theone or more fluid flow calculations to provide a three-dimensional bloodflow and pressure field along the RVOT of the patient. Flow fields maybe produced to simulate diastole, systole, or any intermediate periodwithin the cardiac cycle. Flow field and pressure information, alongwith parameters associated with the patient's RVOT, may be supplied to asolid structural modeling simulation that may predict the shape of theheart valve leaflet structure during multiple points in the cardiaccycle.

After each heart valve leaflet structure model has been analyzed, avalue of a valve performance cost function may be determined based on anperformance of the heart valve leaflet structure model according to theone or more optimization analyses. A heart valve leaflet structureoptimization method may then include providing iterative incrementalchanges to one or more of leaflet modeling parameters and re-modelingthe heart valve leaflet structures. An optimal set of leaflet modelingparameters may thus be found that may minimize a valve performance costfunction. In one non-limiting embodiment, a valve performance costfunction may be based upon the effective orifice area of the heart valveleaflet structure during systole and regurgitant flow during diastole.In another non-limiting embodiment, a valve performance cost functionmay be based on a ratio of the conduit area closed to fluid flow to thearea open to fluid flow. In another non-limiting embodiment, a valveperformance cost function may be based on a rate of valve opening orclosing. In yet another non-limiting embodiment, a valve performancecost function may be based on a ratio of regurgitant flow rate duringdiastole to the forward flow rate during systole.

At the completion of the optimization calculation, a set of heart valveleaflet size parameters may be calculated. In one non-limitingembodiment, a set of heart valve leaflet size parameters may be suppliedto a user by a computing device. Thus, with reference to a two-leafletvalve leaflet structure as illustrated in FIG. 3D, computing devicecalculations may provide values for outer lengths (305 a and 305 b),inner lengths (310 a and 310 b), heights (320 a and 320 b), widths (335a and 305 b), fan structures (315 a and 315 b), fan structure heights(340 a and 340 b), and commissure length (330). A user of the modelingand optimization calculations may then use one or more of thesecomputing device-calculated heart valve leaflet size parameters forfabricating one or more heart valve leaflet structures. For example, auser may use the calculated values for outer lengths, inner lengths,heights, widths, fan structures, fan structure heights, and commissurelength. In an alternative embodiment, a computing device may alsoprovide a heart valve leaflet structure stencil based at least in partupon these calculated heart valve leaflet size parameters. A heart valveleaflet structure stencil may be produced by an output device, such as aprinter, for use by a user. A user may then take the heart valve leafletstructure stencil and apply it to a thin sheet of material for makingthe heart valve leaflet structure, and cut out the heart valve leafletstructure based on the heart valve leaflet structure stencil. The shapesand/or metrics thus calculated may be used by a health care provider, afabricator, or a manufacturing facility to produce a variety of heartvalve structures including, but not limited to, single leaflet,two-leaflet, or three leaflet heart valve structures.

In addition to heart valve leaflet size parameters related to a heartvalve leaflet structure, a user may also receive sinus stencil sizeparameters. Thus, with reference to a two-leaflet valve leafletstructure sinus stencil as illustrated in FIG. 3E, a computing devicecalculations may provide values for outer lengths (305 a′ and 305 b′),inner lengths (310 a′ and 310 b′), heights (320 a′ and 320 b′), widths(335 a′ and 305 b′), and commissure length (330′). In an embodiment inwhich a sinus stencil additionally incorporates fan structures, thesinus stencil size parameters may also include parameters to define thefan structures, including without limitation fan structure heights. Auser of the modeling and optimization calculations may then use one ormore of these computing device-calculated values for fabricating one ormore sinus stencils that may be applied to the inner surface of aconduit for marking the placement of the heart valve leaflet structure,as disclosed above. In another embodiment, a computing device may alsoprovide the sinus stencil based at least in part upon the calculatedsinus stencil size parameters. A sinus stencil provided by a computingdevice may be provided to a user from a printer device associated withthe computing device.

As disclosed above, in one non-limiting embodiment, an artificial heartvalve structure may be composed of a conduit, a heart valve leafletstructure, and one or more conduit sinus structures. In an alternativeembodiment, an artificial heart valve structure may further incorporateone or more biodegradable structures. Such a heart valve structure maybe conveniently referred to as a hybrid tissue-engineered valved conduit(hybrid TEVC). A hybrid TEVC may include, in one non-limiting example, aconduit constructed of synthetic material and having a cross sectionforming a partially closed circle, and a biodegradable structure whichmay be incorporated into the conduit wall to form an enclosed tubularstructure. A hybrid TEVC may also include and one or more heart valveleaflet structures, and one or more conduit sinus structures disposedwithin the conduit.

FIG. 9 illustrates several views of an embodiment of a hybrid TEVC. View900 a illustrates a “back” view of an embodiment of a hybridtissue-engineered valved conduit 905. The material of the conduit 905 asillustrated in view 900 a may be a synthetic biocompatible and/orhemocompatible polymer that may include, as non-limiting examples, PTFEor ePTFE. View 900 a also illustrates a pair of conduit sinus structures902 a and 902 b that may be incorporated into a conduit 905 wall. Nextto the conduit 905 may be observed a portion of a biodegradablestructure 910.

View 900 b illustrates a “front” view of the TEVC. It may be appreciatedthat the conduit may not be completely closed, but may have one or moreconduit breaches 928 along the conduit wall. Each breach may include atleast a pair of conduit breach edges from the from conduit wall. In onenon-limiting embodiment, one or more conduit breaches 928 may extendalong the entire long axis of a conduit. In another embodiment, aconduit breach 928 may extend only partly along the long axis of aconduit. In still another embodiment, multiple conduit breaches 928,each extending along a portion of the long axis of a conduit wall, maybe dispose in a helical pattern. In one non-limiting example, suchmultiple conduit breaches 928, disposed in a helical pattern, mayoverlap along one or more circumferential portions of the conduit wall.In yet another example, such multiple conduit breaches 928, disposed ina helical pattern, may not overlap along any circumferential portions ofa conduit wall. In addition, heart valve leaflets 912 a and 912 b may beobserved in view 900 b. A portion 910 of a biodegradable structure maybe observed next to the body of a hybrid TEVC.

View 900 c illustrates a cross-sectional view of an embodiment of ahybrid TEVC. Two heart valve leaflets 912 a and 912 b may be observed inview 900 c as well. In addition, a portion of a biodegradable structure910 may be observed as being incorporated into the conduit of the hybridTEVC. In one non-limiting embodiment, a biodegradable structure 910 mayhave at least two sides, in which each side may be affixed to a conduitbreach edge. View 900 d illustrates the a biodegradable structure 910affixed into a conduit breach 928 of the hybrid TEVC 905. Biodegradablestructure 910 may be affixed to the conduit breach edges via one or moreof laser beam welding, monocoque technique, heat or chemical welding,and/or the use of an adhesive.

Although FIG. 9 illustrates several views of a hybrid TEVC in which aconduit breach extends essentially along a long axis of the conduit, itmay be appreciated that one or more conduit breaches may be orientedaccording to alternative geometries. In one non-limiting example, aconduit breach may take the form of a helical curve traversing thelength of a conduit. In yet another embodiment, one or more conduitbeaches may traverse essentially one or more circumferences of aconduit. In yet another embodiment, one or more conduit breaches may bedisposed along a conduit wall at one or more angles with respect to thelong axis of the conduit. In one non-limiting embodiment, multipleconduit breaches may form one or more continuous breach structures. Inyet another non-limiting embodiment, multiple conduit breaches may beseparate, and not form a continuous breach structure. In onenon-limiting embodiment, a conduit breach may be composed of a singlestraight line segment. In another non-limiting embodiment, a conduitbreach may be composed of a single curved line segment. In yet anothernon-limiting embodiment, a conduit breach may be composed of a serratedline segment. It may be appreciated that a conduit breach may becomposed of one or more straight or curved line segments arranged in anyconvenient shape.

It may be further understood that one or more biodegradable structuresmay be incorporated into one or more conduit breaches. In onenon-limiting example, as illustrated in FIG. 9, a single biodegradablestructure 910 may be incorporated into the conduit wall along a singleconduit beach 928. In another non-limiting example, multiplebiodegradable structures may be aligned for incorporation into a singleconduit breach. In still another embodiment, multiple biodegradablestructures may be provided, each biodegradable structure beingincorporated into the conduit wall at a separate conduit breach.

A biodegradable structure in the hybrid TEVC may be composed of one ormore materials that may degrade within a body over some period of time.In one non-limiting example, one or more biodegradable structures may bemade from poly(glycerol sebacate). In another non-limiting example, oneor more biodegradable structures may be a composite, combining multiplesynthetic materials. In another non-limiting example, one or morebiodegradable structures may be made from poly(glycerol sebacate)encapsulated by a sheath of poly(caprolactone). In a non-limitingexample, poly(caprolactone) may have been formed using electrospinningtechniques to improve its mechanical and biological properties. Inanother non-limiting example, one or more biodegradable structures mayinclude any other degradable biocompatible and/or hemocompatiblematerial. It may be appreciated that a hybrid TEVC composed of multiplebiodegradable structures may include a number of biodegradablestructures having essentially the same composition. Alternatively,multiple biodegradable structures may include a number of biodegradablestructures having differing compositions.

In one embodiment of a hybrid TEVC, a biodegradable structure may bereplaced over time by autologous tissue, thereby allowing the heartvalve structure to enlarge as the patient grows. In one non-limitingembodiment, a biodegradable structure 910 may be incorporated into aheart valve structure and implanted within a patient. In such anembodiment, cells from a patient may migrate into a biodegradablestructure 910 over time to replace the material from which thebiodegradable structure may be fabricated. In another non-limitingembodiment, a biodegradable structure 910 may be seeded with cells priorto implantation into a patient. Seeded cells may include, withoutlimitation, autologous cells harvested from the patient. Examples ofautologous cells may include, without limitation, one or more of CD34cells, mesenchymal cells, myocytes, smooth muscle cells, endothelialcells, and human cardiac stem cells. In another embodiment, thebiodegradable structure may include collagen fibers. In othernon-limiting embodiments, a biodegradable structure may also includegrowth or other trophic factors, to promoted biocompatibility and/orhemocompatibility, or other biologically active materials to providemore effective therapies.

A hybrid TEVC may be fabricated from a heart valve structure asdisclosed above. A heart valve structure, including one or more heartvalve leaflet structures and or conduit sinus structures, may beobtained. One or more conduit breaches may be fabricated in the conduitwall, each conduit breach having a pair of conduit breach edges. The oneor more conduit breaches may be formed by cutting a conduit wallincluding, but not limited to, slicing, cutting, or heating. Implementsthat may form the one or more conduit breaches may include, withoutlimitation, scissors, a scalpel, a small knife, or a focused laser. Onceone or more conduit breaches have been fabricated in a conduit wall, oneor more biodegradable structures may be incorporated into the one ormore conduit breaches by affixing at least a portion of thebiodegradable structure to each of the conduit breach edges associatedwith each conduit breach. After each biodegradable structure has beenaffixed into a conduit wall breach, an essentially closed tubularstructure composed of the conduit wall and the one or more affixedbiodegradable structures may be formed. The one or more biodegradablestructures may be affixed to the conduit breach edges by any appropriatemeans, including, without limitation, gluing, heat welding, chemicalwelding, and/or suturing.

EXAMPLES Example 1: A Heart Valve Two-leaflet Structure

A heart valve two-leaflet structure, essentially as illustrated anddisclosed in FIG. 3D, was fabricated from expanded PTFE having athickness of about 0.1 mm A two-leaflet structure was designed forintegration into a 20 mm diameter conduit. The heart valve two-leafletstructure was bilaterally symmetric about the commissure, thus measuresof equivalent components between the two leaflets were about the same.The length of each inner sinus edge (equivalent to FIG. 3D 310 a,b) wasabout 16 mm, the height of each leaflet (equivalent to FIG. 3D 320 a,b)was about 15 mm, the width of each baseline (equivalent to FIG. 3D 335a,b) was about 27.7 mm, and each fan structure height (equivalent toFIG. 3D 340 a,b) was about 2.8 mm. The fan structure of each leaflet wassimilar to the structure illustrated as 315 a,b in FIG. 3D, and the fanstructures were bilaterally symmetric about the commissure. In addition,the commissure length (equivalent to FIG. 3D 330) was about 7 mm.

Example 2: Values for Scaling Heart Valve Leaflet Structure Parametersto a Conduit Diameter

FIGS. 3D and 3E illustrate embodiments of a heart valve leafletstructure and a sinus stencil that may be used to mark the attachment ofthe sinus edges to a conduit as part of the method for fabricating aheart valve structure. As disclosed above, the metrics associated withthe elements of the leaflets may be scaled according to the diameter ofthe conduit in which the heart valve leaflet structure may be inserted.Table 1, disclosed below, provides some values for the leaflet metrics,including some non-limiting ranges. The metric entry referencesequivalent structures in FIGS. 3D (for the leaflet) and 3E (for thestencil). Ranges are provided as examples only. The leaflet valuecorresponds to the metric for a heart valve leaflet, The sinus stencilvalue corresponds to the metric for an equivalent sinus stencil. Thevalues in Table 1 are scaling values to conduit diameters, and may beused as multipliers to the conduit diameter to provide the appropriatelength or width. Thus, a heart valve leaflet structure used in a conduitwith a diameter of about 10 mm, may have a height of about 8.1 mm.

TABLE 1 Leaflet Leaflet Sinus Leaflet Metric Value Range Stencil ValueSinus Range Sinus Inner Edge .81 .75-1.0 .77 .7-.9 length Height .77 .7-1.0 .77  .7-1.0 Baseline width 1.38 1.3-1.7 1.28 1.2-1.5 Commissurelength .34 .3-.5 .34 .3-.5 Fan structure height .14 .12-.18 — —

Example 3: Simulation of Blood Flow Through a Heart Valve StructureModel Conduit

Blood flowing through a modeled heart valve structure conduit wasmodeled as an incompressible and Newtonian fluid with constanthemodynamic properties (p=1060 kg/m{circumflex over ( )}3, μ=3.71 E-3Pa·s) without a turbulence model. A cardiovascular blood flow simulatorwith validated 2′-order accurate multi-grid artificial compressibilitynumerical solver was used to evaluate flow through the conduits. Theblood flow was simulated on a high-resolution unstructured Cartesianimmersed boundary grid with finite-difference numerical treatment.

Example 4: Simulation of a Heart Valve Structure

A 20 mm diameter conduit was modeled according to the same geometricparameters which were used in a clinical application (1=15.98 mm, h=15.3mm, w=27.7 mm, c=6.9 mm, F=2.8 mm). A solid model thus generated wasfound to be significantly similar to the actual valve it modeled. Ananalysis of fluid flow through the heart valve structure thus modeleddetermined that regurgitation through the heart valve structure duringdiastole was about 8.27 mL/s. This was determined to represent about7.84% leakage through the valve for a cardiac cycle having a 3.7 L/minflow rate, which may be normal for children.

The present disclosure is not to be limited in terms of the particularembodiments described in this application, which are intended asillustrations of various aspects. Many modifications and variations canbe made without departing from its spirit and scope, as will be apparentto those skilled in the art. Functionally equivalent methods andapparatuses within the scope of the disclosure, in addition to thoseenumerated in this disclosure, will be apparent to those skilled in theart from the foregoing descriptions. Such modifications and variationsare intended to fall within the scope of the appended claims. Thepresent disclosure is to be limited only by the terms of the appendedclaims, along with the full scope of equivalents to which such claimsare entitled. It is also to be understood that the terminology used inthis disclosure is for the purpose of describing particular embodimentsonly, and is not intended to be limiting.

With respect to the use of substantially any plural and/or singularterms in this disclosure, those having skill in the art can translatefrom the plural to the singular and/or from the singular to the pluralas is appropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth in thisdisclosure for sake of clarity. It will be understood by those withinthe art that, in general, terms used in this disclosure, and especiallyin the appended claims (e.g., bodies of the appended claims) aregenerally intended as “open” terms (e.g., the term “including” should beinterpreted as “including but not limited to,” the term “having” shouldbe interpreted as “having at least,” the term “includes” should beinterpreted as “includes but is not limited to,” etc.).

It will be further understood by those within the art that if a specificnumber of an introduced claim recitation is intended, such an intentwill be explicitly recited in the claim, and in the absence of suchrecitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should be interpreted to mean “at least one”or “one or more”); the same holds true for the use of definite articlesused to introduce claim recitations. In addition, even if a specificnumber of an introduced claim recitation is explicitly recited, thoseskilled in the art will recognize that such recitation should beinterpreted to mean at least the recited number (e.g., the barerecitation of “two recitations,” without other modifiers, means at leasttwo recitations, or two or more recitations). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

As will be understood by one skilled in the art, for any and allpurposes, such as in terms of providing a written description, allranges disclosed in this disclosure also encompass any and all possiblesubranges and combinations of subranges thereof. As will also beunderstood by one skilled in the art all language such as “up to,” “atleast,” and the like include the number recited and refer to rangeswhich can be subsequently broken down into subranges as discussed above.Finally, as will be understood by one skilled in the art, a rangeincludes each individual member.

From the foregoing, it will be appreciated that various embodiments ofthe present disclosure have been described for purposes of illustration,and that various modifications may be made without departing from thescope and spirit of the present disclosure. Accordingly, the variousembodiments disclosed are not intended to be limiting, with the truescope and spirit being indicated by the following claims.

What is claimed is:
 1. A valve structure comprising: a conduit having aninner conduit surface; and a leaflet structure having an open state anda closed state, the leaflet structure comprising: a plurality of valveleaflets, each valve leaflet comprising a sinus structure having a sinusedge and a fan structure having a fan edge; wherein at least a portionof the sinus edge is affixed to a portion of the inner conduit surface;and wherein, when the leaflet structure is in the closed state, the fanedges of the plurality of valve leaflets are mutually disposed to form aplurality of valve gaps between at least a portion of the fan edges andat least a portion of the inner conduit surface.
 2. The valve structureof claim 1, wherein, when the leaflet structure is in the open state,the sinus edges of the plurality of valve leaflets and the portion ofthe inner conduit surface are mutually disposed to form a plurality ofvalve gaps between the portion of the sinus edges and the portion of theinner conduit surface.
 3. The valve structure of claim 1, wherein, whenthe leaflet structure is in the open state, the fan edges of theplurality of valve leaflets are mutually disposed to form a plurality ofvalve gaps between at least a portion of the fan edges and at least aportion of the inner conduit surface.
 4. The valve structure of claim 3,wherein, when the leaflet structure is in the open state, the sinusedges of the plurality of valve leaflets and the portion of the innerconduit surface are mutually disposed to form a plurality of valve gapsbetween the portion of the sinus edges and the portion of the innerconduit surface.
 5. The valve structure of claim 1, wherein the fan edgecomprises a fan edge steep portion proximate to the sinus edge, and afan edge gradual portion.
 6. The valve structure of claim 1, wherein atleast a portion of the sinus structure and the portion of the innerconduit surface are nonadjacent, thereby forming a valve sinus boundedat least in part by the portion of the inner conduit surface and theportion of the sinus structure.
 7. The valve structure of claim 1,wherein at least a portion of the valve structure comprises a polymer.8. The valve structure of claim 7, wherein the polymer is afluoropolymer.
 9. The valve structure of claim 1, wherein at least aportion of the valve structure comprises a biodegradable component. 10.The valve structure of claim 1, wherein the conduit is a stent.
 11. Thevalve structure of claim 1, wherein the valve structure furthercomprises a stent.
 12. The valve structure of claim 1, wherein theconduit further comprises at least one conduit sinus structure.
 13. Thevalve structure of claim 12, wherein the at least one conduit sinusstructure is concave relative to the inner conduit surface.